Ocular Inflammation and Oxidative Stress as a Result of Chronic Intermittent Hypoxia: A Rat Model of Sleep Apnea
<p>Experimental design. (1) Rats were randomly assigned to either normoxia or CIH treatment groups. Seven days before the initiation of the CIH protocol, the rats’ home cages were placed into Oxycycler chambers to acclimatize the rats to the chambers under normoxic conditions (21% oxygen). (2) CIH was performed for the CIH group over 8 h starting at 2100 h during the sleep phase of the circadian cycle. The protocol consisted of oxygen reduction from 21% (room air) to 10% oxygen, then returned to 21% oxygen in 6 min cycles per hour (10 cycles/hour) over 8 h/day. For the remaining 16 h, animals were exposed to room air. Normoxic control rats remained in the Oxycycler chambers with room air (21% oxygen) for the duration. (3) Upon completion of the CIH protocol, rats were euthanized and the retinas were analyzed for markers of inflammation and oxidative stress using immunohistochemistry, capillary electrophoresis, thiobarbituric acid reactive substance (TBARS) assay, and Milliplex immunoassay. Schematic created using BioRender.</p> "> Figure 2
<p>(<b>A</b>) Representative immunohistochemistry images assessing expression of HIF-1α (green) in the normoxic (upper panels) and CIH group (lower panels). Sections were also immunolabeled for retinal ganglion cells (RBPMS, magenta) and cell nuclei (DAPI, blue). Scale bar = 50 μm. <span class="html-italic">n</span> (sample size) = 2 rats per group. (<b>B</b>) Capillary electrophoresis (CE) assessing the protein expression of HIF-1α in the CIH group compared to normoxia showed a significant increase in HIF-1α in the CIH group (* <span class="html-italic">p</span> = 0.0198). (<b>C</b>) SIRTUIN-1 (SIRT-1) expression was unchanged across groups (<span class="html-italic">p</span> = 0.5325), as measured by capillary electrophoresis; <span class="html-italic">n</span> = 4 rats per group. Error bars represent mean ± SEM. GCL = ganglion cell layer; INL = inner nuclear layer; ONL = outer nuclear layer. Electropherograms of HIF-1α and SIRTUIN-1 have been included as <a href="#app1-antioxidants-13-00878" class="html-app">Supplementary Materials (Supplementary Figures S1 and S2)</a>.</p> "> Figure 3
<p>CIH induces oxidative stress. (<b>A</b>) Representative images from immunohistochemistry assessing oxidative stress using an antibody directed against 8-OHdG (green) in the normoxic (upper panels) and CIH group (lower panels). Arrows (white) point to RGCs labeled with an antibody against RBPMS (magenta) in the GCL immunolabeled with 8-OHdG. Cell nuclei labeled with DAPI (blue). Scale bar = 50 μm, <span class="html-italic">n</span> = 2 rats per group. (<b>B</b>) Quantified fluorescence intensity of 8-OHdG showed increased nucleic acid-associated oxidative stress damage in the CIH compared to the normoxic group (* <span class="html-italic">p</span> = 0.0483). (<b>C</b>) A TBARS assay quantifying lipid peroxidation in the normoxic group compared to CIH showed no difference across groups (<span class="html-italic">p</span> = 0.8666); <span class="html-italic">n</span> = 6 per group. Error bars represent mean ± SEM. GCL = ganglion cell layer; INL = inner nuclear layer; ONL = outer nuclear layer.</p> "> Figure 4
<p>CIH induces retinal inflammation. (<b>A</b>) Representative immunohistochemistry images showing the expression of the cytokine TNF-α (green) in the normoxic (upper panels) and CIH groups (lower panels). Retinas were colabeled with RBPMS, specific for retinal ganglion cells (magenta), and also stained with DAPI for cell nuclei (blue). (<b>B</b>) Quantification of fluorescence intensity showed increased expression of the cytokine TNF-α in the CIH group compared to normoxia control (*** <span class="html-italic">p</span> = 0.0002; <span class="html-italic">n</span> = 2 rats per group. (<b>C</b>) ELISA showed a significant increase in TNF-α in the CIH group over normoxia (* <span class="html-italic">p</span> = 0.0379, <span class="html-italic">n</span> = 4 rats per group). (<b>D</b>) IHC images of IL-6 (green) in the normoxic (upper panels) and CIH group (lower panels). RBPMS (magenta) and DAPI (blue). (<b>E</b>) Quantifying IL-6 fluorescence intensity showed comparable expression of IL-6 in both normoxia and CIH groups. Error bars represent mean ± SEM. GCL = ganglion cell layer; INL = inner nuclear layer; ONL = outer nuclear layer. Scale bar = 50 μm, <span class="html-italic">n</span> = 2 rats per group.</p> "> Figure 5
<p>(<b>A</b>) Microglia immunolabeled using Iba-1 (green) in the normoxic (upper panels) and CIH group (lower panels). Retinal ganglion cells (magenta) and cell nuclei (DAPI, blue) are labeled for context. Arrows (white) point to Iba1-positive microglia somata. (<b>B</b>) Quantification of fluorescence intensity showed elevated levels of Iba-1 in the CIH group compared to the control (**** <span class="html-italic">p</span> = 0.0001). Error bars represent mean ± SEM. GCL = ganglion cell layer; INL = inner nuclear layer; ONL = outer nuclear layer. Scale bar = 50 μm, <span class="html-italic">n</span> = 2 rats per group.</p> "> Figure 6
<p>(<b>A</b>) Quantification of RGC somata in the normoxic and CIH groups (<span class="html-italic">p</span> = 0.3414) shows that this degree of hypoxia is not sufficient to lead to RGC apoptosis. RGCs were counted in retinal sections, with each point representing a separate section; numbers are expressed as cells per mm of GCL length. (<b>B</b>) Representative immunolabeling from normoxia and (<b>C</b>) CIH retina with RGCs immunolabeled with RBPMS (magenta) and DAPI for cell nuclei (blue). Scale bar = 20 μm.</p> "> Figure 7
<p>Effect of CIH on retinal metabolic enzymes and transporters as measured by capillary electrophoresis. (<b>A</b>) PDK-1 protein was significantly reduced in the CIH group retina compared to the control (* <span class="html-italic">p</span> = 0.03). (<b>B</b>) LDH-A protein levels were not affected by exposure to CIH (<span class="html-italic">p</span> = 0.9692). (<b>C</b>) The expression of GLUT-1 was significantly increased in CIH compared to the normoxia control group (* <span class="html-italic">p</span> = 0.0118). (<b>D</b>) GLUT-3 protein was not different across CIH and normoxia control groups (<span class="html-italic">p</span> = 0.2007). Error bars represent mean ± SEM; GCL = ganglion cell layer; INL = inner nuclear layer; ONL = outer nuclear layer; <span class="html-italic">n</span> = 4 rats per group. Electropherograms of LDH-A, PDK-1, GLUT1, and GLUT 3 have been included as <a href="#app1-antioxidants-13-00878" class="html-app">Supplementary Materials (Supplementary Figures S3–S6)</a>.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. CIH Protocol
2.3. Sample Collection and Preparation
2.4. Immunohistochemistry
2.5. Protein Analysis
2.6. Thiobarbituric Acid Reactive Substance (TBARS) Assay
2.7. Milliplex Inflammation Panel
2.8. Statistics
3. Results
3.1. Chronic Intermittent Hypoxia Increases Hypoxia-Inducible Factor-1α Levels
3.2. Chronic Intermittent Hypoxia Increases Oxidative Stress
3.3. Chronic Intermittent Hypoxia Induces Inflammation
3.4. Chronic Intermittent Hypoxia Induces Microglia Activation
3.5. Effect of Chronic Intermittent Hypoxia on RGC Count
3.6. Effect of Chronic Intermittent Hypoxia on Metabolism
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Antigen | Species | Manufacturer | Catalog Number | Dilution |
---|---|---|---|---|
Hif-1α | Rabbit | Novus | NB100-134 | 1:500 |
Iba-1 | Rabbit | Wako/Sigma | 019-19741 | 1:250 |
RBPMS | Rabbit | Genetex | GTX 118619 | 1:250 |
Mouse | Novus | OTI3B7 | 1:250 | |
TNF-α | Mouse | Abcam | Ab1793 | 1:50 |
8-OHdG | Mouse | QED Bioscience | 12501 | 1:100 |
IL-6 | Rabbit | Invitrogen | PA5-120041 | 1:100 |
Antigen | Species | Manufacturer | Catalog Number | Dilution |
---|---|---|---|---|
Hif-1α | Rabbit | Novus | NB100-134 | 1:25 |
PDK1 | Rabbit | Cell Signaling | C47H1 | 1:100 |
LDH-A | Rabbit | Novus | NBP1-48336 | 1:100 |
SIRT-1 | Rabbit | Novus | MBP2-27205 | 1:100 |
GLUT 1 | Rabbit | Novus | NB110-39113 | 1:50 |
GLUT 3 | Mouse | R&D Systems | MAB1415 | 1:25 |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Donkor, N.; Gardner, J.J.; Bradshaw, J.L.; Cunningham, R.L.; Inman, D.M. Ocular Inflammation and Oxidative Stress as a Result of Chronic Intermittent Hypoxia: A Rat Model of Sleep Apnea. Antioxidants 2024, 13, 878. https://doi.org/10.3390/antiox13070878
Donkor N, Gardner JJ, Bradshaw JL, Cunningham RL, Inman DM. Ocular Inflammation and Oxidative Stress as a Result of Chronic Intermittent Hypoxia: A Rat Model of Sleep Apnea. Antioxidants. 2024; 13(7):878. https://doi.org/10.3390/antiox13070878
Chicago/Turabian StyleDonkor, Nina, Jennifer J. Gardner, Jessica L. Bradshaw, Rebecca L. Cunningham, and Denise M. Inman. 2024. "Ocular Inflammation and Oxidative Stress as a Result of Chronic Intermittent Hypoxia: A Rat Model of Sleep Apnea" Antioxidants 13, no. 7: 878. https://doi.org/10.3390/antiox13070878